The present invention relates to the delivery of physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy.
It is desirable to provide a new route of administration for physiologically active compounds that rapidly produces peak plasma concentrations of the compound. The provision of such a route is an object of the present invention.
The present invention relates to the delivery of physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. Preferably, the particles comprise at least 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine.
Typically, the aerosol has a mass of at least 1 xcexcg. Preferably, the aerosol has a mass of at least 10 xcexcg. More preferably, the aerosol has a mass of at least 20 xcexcg.
Typically, the aerosol particles comprise less than 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products. Preferably, the particles comprise less than 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products.
Typically, the aerosol particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, where the aerosol comprises chlordiazepoxide, the aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 40 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 30 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 20 mg/L.
Typically, where the aerosol comprises betahistine, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 50 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 30 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 20 mg/L.
Typically, where the aerosol comprises clonidine, the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 2 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.03 mg/L and 1.5 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 1 mg/L.
Typically, where the aerosol comprises testosterone, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 20 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.
Typically, where the aerosol comprises conjugated estrogens or estrogen esters, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 5 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 2 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 1.5 mg/L.
Typically, where the aerosol comprises conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters, the aerosol has an inhalable aerosol drug mass density of between 0.001 mg/L and 0.2 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.002 mg/L and 0.1 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.004 mg/L and 0.05 mg/L.
Typically, where the aerosol comprises hyoscyamine, the aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 1 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.025 mg/L and 0.75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 0.5 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.
Typically, the aerosol is formed by heating a composition containing chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. More preferably, the composition comprises 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine.
Typically, the delivered aerosol particles comprise at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. Preferably, the particles comprise at least 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine.
Typically, the delivered aerosol has a mass of at least 1 xcexcg. Preferably, the aerosol has a mass of at least 10 xcexcg. More preferably, the aerosol has a mass of at least 20 xcexcg.
Typically, the delivered aerosol particles comprise less than 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products. Preferably, the particles comprise less than 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradation products.
Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.85. More preferably, the geometric standard deviation is less than 2.7.
Typically, the particles of the delivered condensation aerosol comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, at least 50 percent by weight of the aerosol is amorphous in form, wherein crystalline forms make up less than 50 percent by weight of the total aerosol weight, regardless of the nature of individual particles. Preferably, at least 75 percent by weight of the aerosol is amorphous in form. More preferably, at least 90 percent by weight of the aerosol is amorphous in form.
Typically, where the aerosol comprises chlordiazepoxide, the delivered aerosol has an inhalable aerosol drug mass density of between 1 mg/L and 40 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 30 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 3 mg/L and 20 mg/L.
Typically, where the aerosol comprises betahistine, the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 50 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 2 mg/L and 30 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 5 mg/L and 20 mg/L.
Typically, where the delivered aerosol comprises clonidine, the aerosol has an inhalable aerosol drug mass density of between 0.02 mg/L and 2 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.03 mg/L and 1.5 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 1 mg/L.
Typically, where the aerosol comprises testosterone, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 20 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.
Typically, where the aerosol comprises conjugated estrogens or estrogen esters, the delivered aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 5 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 2 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.15 mg/L and 1.5 mg/L.
Typically, where the aerosol comprises conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters, the delivered aerosol has an inhalable aerosol drug mass density of between 0.001 mg/L and 0.2 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.002 mg/L and 0.1 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.004 mg/L and 0.05 mg/L.
Typically, where the aerosol comprises hyoscyamine, the delivered aerosol has an inhalable aerosol drug mass density of between 0.01 mg/L and 1 mg/L. Preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.025 mg/L and 0.75 mg/L. More preferably, the delivered aerosol has an inhalable aerosol drug mass density of between 0.05 mg/L and 0.5 mg/L.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
Typically, the delivered aerosol is formed at a rate greater than 0.25 mg/second. Preferably, the aerosol is formed at a rate greater than 0.5 mg/second. More preferably, the aerosol is formed at a rate greater than 1 or 2 mg/second.
Typically, where the aerosol comprises chlordiazepoxide, between 1 mg and 40 mg of chlordiazepoxide is delivered to the mammal in a single inspiration. Preferably, between 2 mg and 30 mg of chlordiazepoxide is delivered to the mammal in a single inspiration. More preferably, between 3 mg and 20 mg of chlordiazepoxide is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises betahistine, between 0.5 mg and 50 mg of betahistine is delivered to the mammal in a single inspiration. Preferably, between 2 mg and 30 mg of betahistine is delivered to the mammal in a single inspiration. More preferably, between 5 mg and 20 mg of betahistine is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises clonidine, between 0.02 mg and 2 mg of clonidine is delivered to the mammal in a single inspiration. Preferably, between 0.03 mg and 1.5 mg of clonidine is delivered to the mammal in a single inspiration. More preferably, between 0.05 mg and 1 mg of clonidine is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises testosterone, between 0.1 mg and 20 mg of testosterone is delivered to the mammal in a single inspiration. Preferably, between 0.2 mg and 10 mg of testosterone is delivered to the mammal in a single inspiration. More preferably, between 0.5 mg and 5 mg of testosterone is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises conjugated estrogens or estrogen esters, between 0.05 mg and 5 mg of conjugated estrogens or estrogen esters is delivered to the mammal in a single inspiration. Preferably, between 0.1 mg and 2 mg of conjugated estrogens or estrogen esters is delivered to the mammal in a single inspiration. More preferably, between 0.15 mg and 1.5 mg of conjugated estrogens or estrogen esters is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters, between 0.001 mg and 0.2 mg of conjugated conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters is delivered to the mammal in a single inspiration. Preferably, between 0.002 mg and 0.1 mg of conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters is delivered to the mammal in a single inspiration. More preferably, between 0.004 mg and 0.05 mg of conjugated estradiol, estradiol esters, ethinyl estradiol, or ethinyl estradiol esters is delivered to the mammal in a single inspiration.
Typically, where the aerosol comprises hyoscyamine, between 0.01 mg and 1 mg of hyoscyamine is delivered to the mammal in a single inspiration. Preferably, between 0.025 mg and 0.75 mg of hyoscyamine is delivered to the mammal in a single inspiration. More preferably, between 0.05 mg and 0.5 mg of hyoscyamine is delivered to the mammal in a single inspiration.
Typically, the delivered condensation aerosol results in a peak plasma concentration of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).
In a kit aspect of the present invention, a kit for delivering chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine; and, b) a device that forms a chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine containing aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 10 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine.
Typically, the device contained in the kit comprises: a) an element for heating the chlordiazepoxide, betahistine, clonidine, testosterone, conjugated estrogens, estrogen esters, estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.